Project Summary Postoperative cognitive dysfunction (POCD) is common in elderly patients after major surgery. As the population of geriatric surgical patients grows, it is imperative to understand the pathogenic mechanisms underlying POCD and develop treatment strategies. Accumulating evidence suggests that general anesthetics administered during surgery at the extremes of age could have long-lasting detrimental effects on the nervous system. Indeed, our studies of cortical circuits have revealed various undesired effects of general anesthesia on both developing and aging brains after surgery, including changes in synaptic protein, abnormal dendritic spine plasticity and neuronal function, as well as impaired neurocognitive performance. These anesthesia- induced changes in neuronal plasticity and function could have an important role in the development of POCD, particularly in aging individuals. In addition to anesthetic drugs, immune cells and signaling pathways activated after surgery may also have profound impacts on brain functions and contribute to POCD. Using in vivo longitudinal imaging of neuronal structure and function, we will first determine how general anesthesia leads to long-lasting changes in neuronal circuits and the delayed neurocognitive recovery after surgery. Combined with an immunological toolset including bone marrow chimera, in vivo cell depletion and adoptive cell transfer, we will further determine the neuroimmune mechanisms mediating neural circuit dysfunction in POCD. We will also manipulate neurotransmission and immune signaling pathways to facilitate postoperative cognitive recovery. Together, our proposed experiments will likely reveal the important functions of anesthesia and immune activation in POCD and help the development of therapeutic treatment.